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Sepsis Updates
1. Beka Aberra M.D
Internal Medicine Resident [R1]
Moderator Dr. Tola Bayissa [Consultant Internist, Pulmonologist]
2. 1. Introduction
2. Epidemiology
3. Pathophysiology
4. Clinical Manifestations
5. Major Complications
6. Diagnostic Work up of Septic Patient
7. Principles of Sepsis/Septic Shock Management
8. Prognosis and Prevention
9. References
11/28/2018 2
3. Sepsis is one of the Oldest and most Elusive syndromes in medicine.
Hippocrates 4th Century BC
“Sepsis (ση´ψις) was the process of decay/decomposition of organic
matter.[Flesh rotting, swamps generating foul air, and wounds
festering].”
Galen later considered Sepsis a Laudable event, necessary for
wound healing.
Pasteur - Coined term “Microbes”
Pfeiffer - Coined Endotoxin 20th Century [V. Cholera].For All Grm-
ves
Hugo shotmuller- Paved the way to Modern definition of Sepsis
5. A Large International collaboration
was established to educate people
about sepsis and to improve patient
outcomes with sepsis, entitled
“Surviving Sepsis Campaign”
In 1991, an International consensus
panel defined sepsis as a systemic
inflammatory response to infection.
In 2001, a second consensus panel
endorsed most of these concepts of
SIRS.
These definitions don’t allow precise
staging or prognostication of host
response and in [2012] practical
modification of definitions.
The Surviving Sepsis campaign and the
Institute for Healthcare improvement have
teamed up to achieve a 25% reduction in sepsis
mortality by 2009.
Six Pronged approach
• Building awareness of Sepsis by Educating
Healthcare Professionals
• Improving Early Diagnosis
• Increasing the use of appropriate treatment
• Improving Post ICU care
• Developing Guidelines of care
• Facilitating data collection for audit/feedback.
6. CHANGES IN
INTERNATIONAL
GUIDELINESepsis 2
Sepsis = SIRS + Infection
Infection sepsis severe sepsis
septic shock MODS
Sepsis 3
Sepsis= Infection + >2 SOFA
score from baseline(MR=10%
NO Severe sepsis
7. Sepsis is redefined as :
“Life-Threatening Organ Dysfunction caused by a
Dysregulated Host response to Infection.”
JAMA, Feb. 23, 2016: Sepsis-3, New criteria for
defining sepsis
14. SOFA SCORE VARIABLES
Mortality rate increases as number of organs with
dysfunction increases. Unlike other scores, the worst
value on each day is recorded.
A key difference is in the cardiovascular component;
instead of the composite variable, the SOFA score
uses a treatment-related variable (dose of
vasopressor agents).
Maximal (highest total) SOFA score: is the sum of
highest scores per individual during the entire ICU
stay. A score of >15 predicted mortality of 90%.
Mean SOFA score: is the average of all total SOFA
scores in the entire ICU stay.
Delta SOFA (ΔSOFA) score: maximum SOFA –
admission SOFA
15.
16.
17.
18. EPIDEMIOLOGY
Sepsis is a contributing factor in >200,000 deaths per year in the
US.
The incidence of severe sepsis and septic shock has increased over
the past 30 years, and the annual number of cases is now >750,000
(~3 per 1000 population).
Approximately two-thirds of the cases occur in patients with
significant underlying illness.
Septicemia was the most expensive condition seen in US hospital
stays in 2011….20.3 billion dollar for nearly 1.1 million
hospitalizations.
Costs have Quadrupled since 1997 with an 11.5 % annual increase.
19. WHY THE BURDEN OF SEPSIS
INCREASING?
Increasing geriatric population
Increasing number of immunocompromised host
Increasing antimicrobial use [Drug Resistant Organisms]
Increasing use of Immunosuppressive’s
Increasing metabolic disorders [NCDs]
Increasing use of indwelling catheters and mechanical ventilators
20.
21. ETIOLOGIES
In a prevalence study of 14,414 patients in ICUs from 75
countries in 2007, 51% of patients were considered
infected
Respiratory infection was most common (64%)
Microbiologic results were positive in 70% of individuals
considered infected
62% were gram-negative bacteria (Pseudomonas species and
E.coli were most common)
47% were gram positive bacteria (Staphylococcus aureus was
most common)
19% were fungi (Candida species)
Bacteremia arising from a Pulmonary or Abdominal source
was eightfold more likely to be associated with severe
sepsis than was bacteremia UTI.
24. RESULTS: From a total of 95 suspected septic cases involved in this research,
15 (15.8 %) were positive to eight different types of bacteria.
Gram positive organisms were isolated in 53.3 % of these episodes with Staphylococcus
aureus being the most frequent, while
Gram negative accounted for the remaining 46.7 % with Escherichia coli being the
commonest isolate among Gram negative bacteria.
The isolates showed high rates of resistance to most antibiotics tested in-vitro. The ranges
of resistance to Gram positive bacteria were 0 % to 100 %, and to Gram negative from 14.3
% to 85.7 %.
In our study multidrug resistance (resistance to three or more drugs) was
observed in 80 % of isolates. Of this 87.5% and 71.4 % accounted for Gram
positive and Gram negative bacteria respectively (P=0.438)
26. PATHOGENESIS The balance of
proinflammatory and
anti-inflammatory
mediators regulates
the inflammatory
processes, including
adherence,
chemotaxis,
phagocytosis of
invading bacteria,
bacterial killing, and
phagocytosis of debris
from injured tissue.
The End Result will
be Tissue Repair and
Healing.
27. SYSTEMIC EFFECTS OF
SEPSIS —The precise
mechanism of cellular injury
is not understood, but its
occurrence is indisputable
as autopsy studies have
shown widespread
endothelial and
parenchymal cell injury.
Mechanisms proposed to
explain the cellular injury
include: Tissue ischemia
(insufficient oxygen
relative to oxygen need),
Cytopathic injury (direct
cell injury by
proinflammatory
mediators and/or other
products of inflammation),
and an Altered rate of
Apoptosis (programmed
cell death).
28.
29. Many investigators have favored widespread vascular
endothelial injury as the major mechanism for multiorgan
dysfunction.
In keeping with this idea, one study found high numbers of
vascular endothelial cells in the peripheral blood of septic
patients.
Leukocyte-derived mediators and platelet-leukocyte-fibrin thrombi
may contribute to vascular injury, but the vascular endothelium
also seems to play an active role.
30. Lewis Thomas's Theory
11/28/2018
“The Micro-Organisms that seem to have it in
for us . . . turn out . . . to be rather more like
bystanders. . . . It is our Own Response to their
presence that Makes the Disease.”
33. The Pathogenesis of Sepsis thus may differ according to
1. The Infecting Microbe,
2. The Ability of the host's innate defense mechanisms to
sense it.
3. The Site of the primary infection,
4. The Presence or absence of immune defects, and
5. The Prior physiologic status of the host.
6. The Genetic factors with [TLR4/TNF-a/IFN-g]
Polymorphisms.
34. CLINICAL
MANIFESTATIONS Varies depending on the site of Primary infection
Hypothermia Vs Febrile
Absence of fever
In neonates, elderly, uremic or alcoholic patients
Hyperventilation → Respiratory alkalosis
Often an early sign of the septic response
Change in mentation-Disorientation, Confusion [Septic Delirium]
Skin rash [petechial/purpura]-Meningococcemia
Ecthyma Gangrenosum [Pseudomonas] in Neutropenic Pts
35. COMPLICATIONS
Cardiopulmonary
ARDS
ALI or ARDS develops in ~50%
Depression of Myocardial function, manifested as increased end
diastolic and systolic ventricular volumes with a decreased EF.
Adrenal Insufficiency –CIRCI
N. meningitides bacteremia, disseminated TB, AIDS (with
CMV,MAC, or Histoplasma Capsulatum disease)
36. COMPLICATIONS…
Renal Complications
Oliguria, azotemia, proteinuria, and nonspecific urinary casts,
inappropriate polyuria
Most are due to ATN induced by hypovolemia, arterial
hypotension, or toxic drugs
Some patients also have GN, renal cortical necrosis, or interstitial
nephritis
High mortality rate
37.
38.
39. Remarkably, poorly functioning "septic" organs usually appear
normal at autopsy.
There is typically very little necrosis or thrombosis, and
apoptosis is largely confined to lymphoid organs and the GIT.
Moreover, organ function usually returns to normal if patients
recover.
These points suggest that organ dysfunction during severe
sepsis has a basis that is principally biochemical, not
structural.
40. DIAGNOSIS
No specific single diagnostic test for sepsis
Under recognition
“Need of SEPSIS-SCORE’S is Here”
A patient with suspected or proven infection include [Fever or
hypothermia, Tachypnea, Tachycardia, and Leukocytosis or
leukopenia]; acutely altered mental status, thrombocytopenia, an
elevated blood lactate level, respiratory alkalosis, or hypotension
also should suggest the diagnosis.
In one study, 36% of patients with severe sepsis had a normal temperature, 40%
had a normal RR, 10% had a normal PR, and 33% had normal WBC.
42. Appropriate cultures before antimicrobial therapy as soon as possible
(<45 minutes) (Grade 1C).
At least two sets of blood cultures (both aerobic and anaerobic bottles)
before antimicrobial therapy.
Imaging studies be performed promptly in attempts to confirm a
potential source of obscure infection.
Bedside studies, such as ultrasound, may avoid patient transport
(Ungraded)
DIAGNOSIS
43. CLINICAL CRITERIA FOR
SEPTIC SHOCK 2016
DESPITE ADEQUATE FLUID RESUSCITATION
VASOPRESSOR NEEDED TO MAINTAIN MAP >_65mm Of Hg
AND
LACTATE >2 MMOL/LIT [18 mg/dl]
44. During the “Hypo dynamic" period, . [SVR-NL; CO-
Low] the blood lactate concentration is elevated and
central venous oxygen saturation is low
Fluid administration is usually followed by the
“Hyper dynamic, Vasodilatory phase” during which
[SVR-Low ;Cardiac Output is normal (or even high)]
and oxygen consumption declines despite adequate
oxygen delivery. The blood lactate level may be
normal or increased, and normalization of central
venous oxygen saturation may reflect improved
oxygen delivery.
45. MANAGEMENT OF SEPSIS
FLUIDS
VASOACTIVE DRUGS TO MAINTAIN MAP
ANTIBIOTICS
SOURCE IDENTIFICATION AND CONTROL
PLACE OF STEROIDS
LUNG PROTECTIVE VENTILATION
EARLY ORGAN SUPPORT
AND MANY MORE…
BUT THE MOST IMPORTANT IS A SYSTEMATIC
APPROACH …..“Bundle Approach”
46. The “Sepsis Bundle” has been central to the implementation of the
Surviving Sepsis Campaign (SSC) from the fist publication of its
evidence-based guidelines in 2004 through subsequent editions.
“Bundles in Health care”… Selected set of elements of care distilled from
evidence based practice guidelines that when implemented as a group
have an effect on outcome rather than as individuals alone.
When introduced, the bundle elements were designed to be updated as
indicated by new evidence and have evolved accordingly. In response to
the publication of “Surviving Sepsis Campaign: International Guidelines
for Management of Sepsis and Septic Shock: 2016” with 3/6/24 hr
bundles, a revised “hour-1 bundle” has been developed and is presented
below on SSC 2018.
47. • Next 24 Hrs SSC Management
Bundle
• Low Dose Steroids
• Act Protein C
• Glycemic Control
• Lung Protective Ventilator
Strategy [5-8 ml/kg];
Pplat<30cmh20 to Avoid
Volutrauma/Barotrauma
48. The most important change in the revision of the SSC bundles is that the 3-h and
6-h bundles have been combined into a single “hour-1 bundle” with the explicit
intention of beginning resuscitation and management immediately.
More than 1 hour may be required for resuscitation to be completed, but initiation
of resuscitation and treatment, such as obtaining blood for measuring lactate and
blood cultures, administration of fluids and antibiotics, and in the case of life-
threatening hypotension, initiation of vasopressor therapy, are all begun
immediately.
49.
50.
51. Administer IV Fluid
Early effective fluid resuscitation is crucial for the stabilization of sepsis-
induced tissue hypoperfusion or septic shock. Given the urgent nature of
this medical emergency, initial fluid resuscitation should begin
immediately upon recognizing a patient with sepsis and/or hypotension
and elevated lactate, and completed within 3 hours of recognition.
The guidelines recommend this should comprise a minimum of 30 mL/kg of
intravenous crystalloid fluid.
Because some evidence indicates that a sustained positive fluid balance
during ICU stay is harmful, fluid administration beyond initial
resuscitation requires careful assessment of the likelihood that the patient
remains fluid responsive.
58. IVF
RECOMMENDATIO
N Initial fluid challenge ≥ 1000 mL of crystalloids or
minimum of 30 mL/kg of crystalloids in the 1st 4-6
hours
(Strong recommendation; Grade 1C).
Crystalloids is the initial fluid for resuscitation
(Strong recommendation; Grade 1A).
Adding albumin to the initial fluid resuscitation
(Weak recommendation; Grade 2B).
59. ALBUMIN AND SALINE FOR FLUID
RESUSCITATION IN THE ICU (SAFE TRIAL)
RCT ~ 7,000 pts in 16
Australian/NZ ICUs
Excluded pts after cardiac
surgery, liver transplant and
burns
4% albumin or NS
No significant difference:
• 28-day mortality
• New organ failure,
duration of CRRT, or
mechanical ventilation
• ICU and Hospital LOS
NEJM 2004;350:2247-2256
Crystalloids have a much larger
volume of distribution compared
to colloids
Crystalloid resuscitation requires
more fluid to achieve the same
endpoints as colloid
Crystalloids result in more edema
60. Apply Vasopressors
Urgent restoration of an adequate perfusion pressure to the vital
organs is a key part of resuscitation. This should not be delayed.
If blood pressure is not restored after initial fluid resuscitation, then
vasopressors should be commenced within the fist hour to achieve
mean arterial pressure (MAP) of ≥ 65 mm Hg.
The physiologic effects of vasopressors and combined
inotrope/vasopressor selection in septic shock are outlined in a large
number of literature reviews.
61. INOTROPES TO
USE?
Norepinephrine as the first choice
( Grade 1B)
Adding or substituting epinephrine when an additional
drug is needed
(Strong recommendation; Grade 1B).
Dopamine only in highly selected patients at very low
risk of arrhythmias or low heart rate
(Weak recommendation; Grade 2C).
Dobutamine infusion be started or added with low
cardiac output) or ongoing signs of hypoperfusion, even
after adequate intravascular volume
(Strong recommendation; Grade 1C)
Vasopressin 0.03 units/min may be added
(Weak recommendation; Grade 2A)
62. DOCUMENT REASSESSMENT OF
VOLUME STATUS AND TISSUE
PERFUSION WITH
• Repeat Focused Exam (after Initial Fluid Resuscitation)
CLINICALLY: including vital signs [MAP], Cardiopulmonary, capillary refill,
pulse, and skin findings.
LABORATORY [Lactate Clearance/ABG/OFTs/Microbiology]
HEMODYNAMICALLY
Static Assessment of Fluid Responsiveness
Measure CVP
Measure ScvO2
Dynamic assessment of Fluid Responsiveness with Passive Leg raise or Fluid
challenge Respiratory changes in the vena caval diameter, radial artery pulse
pressure, aortic blood flow peak velocity, left ventricular outflow tract velocity-time
integral, and brachial artery blood flow velocity are considered dynamic measures of
fluid responsiveness.
Bedside Cardiovascular ultrasound
Bedside Sonologic assessment of Volume status is prioritized.
63.
64. Obtain Blood Cultures Prior to Antibiotics
Sterilization of cultures can occur within minutes of the
fist dose of an appropriate antimicrobial, so cultures must
be obtained before antibiotic administration to optimize
the identification of pathogens and improve outcomes.
Appropriate blood cultures include at least two sets
(aerobic and anaerobic).
Administration of appropriate antibiotic therapy should
not be delayed in order to obtain blood cultures.
65. Administer Broad Spectrum Antibiotics
Empiric broad-spectrum therapy with one or more intravenous
antimicrobials to cover all likely pathogens should be started
immediately for patients presenting with sepsis or septic shock.
Empiric antimicrobial therapy should be narrowed once pathogen
identification and sensitivities are established, or discontinued if
a decision is made that the patient does not have infection.
If infection is subsequently proven not to exist, then
antimicrobials should be discontinued.
66.
67.
68. ANTIMICROBIAL THERAPY
The administration of effective intravenous
antimicrobials as soon as possible , but never beyond the
first hour of recognition of SEPSIS
Initial empiric anti-infective therapy include one or more
drugs that have activity against all likely pathogens.
The antimicrobial regimen should be reassessed daily for
potential de-escalation to prevent the development of
resistance, to reduce toxicity, and to reduce costs (Grade
1B).
69. ANTIBIOTICS
• Abx within 1 hr hypotension: 79.9% survival
• Survival decreased 7.6% with each hour of
delay
• Mortality increased by 2nd hour post hypotension
• Time to initiation of Antibiotics was the single strongest
predictor of outcome
70. Evaluate patients for focus of infection
amenable to source control measures
Drainage of an abscess or local focus
of infection
Debridement of infected necrotic
tissue
Removal of a potentially infected
device
Definitive control of a source of
ongoing microbial contamination
Source Control???
Grade 1C
71. Measure Lactate Level
While serum lactate is not a direct measure of tissue perfusion, it can
serve as a surrogate, as increases may represent tissue hypoxia,
accelerated aerobic glycolysis driven by excess beta-adrenergic
stimulation, or other causes associated with worse outcomes.
Randomized controlled trials have demonstrated a significant reduction
in mortality with Lactate Guided Resuscitation.
If initial lactate is elevated (> 2mmol/L), it should be remeasured within
2−4 h to guide resuscitation to normalize lactate in patients with
elevated lactate levels as a marker of tissue hypoperfusion.
72. LACTATE-PROGNOSTIC
VALUE High lactate still a marker
of severe physiological
stress and risk of death
High lactate often not
hypoxia related but
represents metabolic
changes of severe stress
More Objective surrogate for
Tissue Perfusion as
compared with Physical
Examination or Urine output.
73. PLACE OF STEROIDS???
IV hydrocortisone at a dose of 200 mg per day should be
given only to adult septic shock patients after it has been
confirmed that their BP is poorly responsive to fluid
resuscitation and vasopressor therapy.
Grade 2C.
For 5-7 days and slowly tapering and d/c
Crit Care Med 2013 SSC Update
74. Corticus Study
Multicenter, double-blind, RCT
52 ICUs, March 2002 – Nov 2005 (3 ½ yrs)
500 pts
Pts > 18 yrs with sepsis and onset of shock
within the previous 72h (SBP < 90 despite
fluids or need for vasopressors for > 1 hour)
Hydrocortisone or Placebo:
50 mg IV q 6h x 5 days
50 mg IV q 12h on days 6 to 8
50 mg IV q 24h on days 9 to 11 then stopped
Sprung C, et al. NEJM 2008;358:111-24
76. CORTICUS: Conclusions
Hydrocortisone RX
•Did not decrease mortality
•Decreased time to shock reversal
•Was assoc. with an increased incidence of:
• Superinfections, including new episodes of
sepsis or septic shock
• Hyperglycemia
• Hypernatremia
Sprung C, et al. NEJM 2008;358:111-24
77. • 80% of pts require
MV
• TV of 6 ml /kg
• Maintain plateau
pressures ≤30 cm
H2O
• Prone positioning be
used in severe
ARDS with a
Pao2/Fio2 ratio ≤
100 mm Hg
• Elevated 30-45°
• Higher PEEP .
78. 0
5
10
15
20
25
30
35
40
6 ml/kg
12 ml/kg
%Mortality
ARDS net Mechanical
Ventilation Protocol
Results: Mortality
. N Engl J Med 2000;342:1301-1378
The ARDS net trial
compared 6 ml/kg ideal
body weight vs. 12 ml/kg
ideal body weight (low tidal
volume/high tidal volume
comparison).
The low tidal volume
group demonstrated a
significant decrease in
mortality.
79. Early enteral nutrition should be given
in patients with sepsis or septic shock
who can tolerate enteral feeding.
Both trophic (500 kcal/day limit) and
full enteral feeds may be appropriate
in certain circumstances;
There is No Longer a
Recommendation to avoid full
enteral feeds during the First Week
in all patients with Sepsis or Septic
Shock.
80. BLOOD PRODUCT ADMINISTRATION
Transfuse PRBC only when Hgb<7.0 g/dL to target a hemoglobin
concentration of 7.0 to 9.0 g/dL in adults (Grade 1B).
The Transfusion Requirements In Septic Shock (TRISS) trial addressed
a transfusion threshold of 7 g/dL versus 9 g/dL in septic shock patients
after admission to the ICU). Results showed similar 90-day mortality,
ischemic events, and use of life support in the two treatment groups
with fewer transfusions in the lower-threshold group.
NO Erythropoietin in Sepsis. NO FFP to correct lab abnormality in
absence of Bleeding or planned invasive procedure.
Platelet transfusion –
<10,000 in absence of bleeding; <20,000 if bleeding risk high; <50,000 if planned
procedure, active bleeding or surgery
81. Glucose control- upper blood glucose <180mg/dl
Renal replacement therapy- CRRT or IHD only for
definitive indications.
VTE prophylaxis-daily pharmacoprophylaxis against
VTE unless there is contraindication.
Stress Ulcer prophylaxis-use H2 BLOCKER OR PPI
to patients with bleeding risk.
Setting goal of care - goals of care and prognosis
should be discussed with patient and family
82. SUMMARY
Previous iterations of the sepsis bundle were introduced as a means
of providing education and improvement related to sepsis
management.
The literature supports the use of sepsis bundles for improving
outcomes in patients with sepsis and septic shock.
This new sepsis “hour-1 bundle,” based on the 2016 SSC Guidelines,
should be introduced to Emergency department and ICU staff as the
next step of ever-improving tools in the care of patients with sepsis
and septic shock; as we all work to lessen the global burden of
sepsis.
83. PROGNOSIS
Approximately 20–35% of patients with Sepsis and 40–60% of
patients with septic shock die within 30 days.
Others die within the ensuing 6 months.
Case–fatality rates are similar for culture-positive and culture-
negative severe sepsis. Culture Positive Sepsis, Antibiotic
Resistance was Linked to Higher Mortality.
Age and prior health status are important risk factors aswell.
Septic shock is also a strong predictor of both short- and long-term
mortality.
85. A number of potential therapies for sepsis appear promising in animal models, but
have not yet been adequately studied in humans.
These include toll-like receptor antagonists and neutralizing antibodies,
talactoferrin, interferon gamma, macrophage migration inhibition factor neutralizing
antibody, and a synthetic peptide that inhibits bacterial super antigen-induced
expression of certain proinflammatory genes.
Other potential therapies for sepsis have been studied in humans, but have provided
conflicting results and require additional investigations to clarify their effects.
These include Polyclonal Intravenous Immune Globulin (IVIG), Interleukin-1
receptor antagonists, Hemoperfusion through adsorptive materials or membranes,
Plasma exchange, Whole blood exchange, Coupled plasma filtration adsorption,
Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), Hemofiltration,
Anticoagulants, Naloxone, Pentoxifylline, and Statins.
Potential therapies that require further validation of benefit in patients with septic
shock include therapy with the short-acting beta blocker, esmolol.
93. PREVENTION
Treat localized nosocomial infections more aggressively
Reducing the number of invasive procedures undertaken, by
limiting the use (and duration of use) of indwelling vascular
and bladder catheters
Reducing the incidence and duration of profound neutropenia
Avoid Indiscriminate use of antimicrobial agents and
glucocorticoids
Optimal infection-control measures
Hand hygiene
Limiting individual getting access to ICU
94.
95. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and
Septic Shock: 2018
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and
Septic Shock: 2016
Third international consensus on definitions for sepsis and septic shock (sepsis-3)
Harrisons principles of internal medicine 19th edition
Up to date 2018
NEJM, Review of articles on Sepsis and Septic shock, 2013
The epidemiology of sepsis and septic shock in US 1997-2001,NEJM:2003.
Memorial care health system sepsis update 2017.
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